Method for producing carboxamides

ABSTRACT

The present invention relates to a novel process for preparing known fungicidally active 1,3-dimethyl-5-fluoro-1H-pyrazole-4-carboxamides from the corresponding acid fluoride and aniline derivatives in the absence of an acid acceptor.

The present invention relates to a novel process for preparing known fungicidally active 1,3-dimethyl-5-fluoro-1H-pyrazole-4-carboxamides from the corresponding acid fluoride and aniline derivatives in the absence of an acid acceptor.

It is already known that 1,3-dimethyl-5-fluoro-1H-pyrazole-4-carboxamides are obtained by reacting the corresponding acid fluoride with the desired aniline derivative (cf. EP-A 0 776 889). According to this description, preference is given to using bicyclic tertiary amines such as diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU) as an acid acceptor. The reaction with DABCO affords only a yield of 80%. Moreover, DABCO is unsuitable for industrial scale implementations, since this reagent is very expensive and cannot be recycled.

It has now been found that carboxamides of the formula (I)

in which

-   R is C₃-C₁₂-cycloalkyl, C₃-C₂₂-cycloalkenyl, C₆-C₁₂-bicycloalkyl,     C₂-C₁₂-oxacycloalkyl, C₄-C₁₂-oxacycloalkenyl, C₃-C₁₂-thiacycloalkyl,     C₄-C₁₂-thiacycloalkenyl, C₂-C₁₂-azacycloalkyl, each of which may     optionally be mono- or polysubstituted, identically or differently,     by C₁-C₈-alkyl, C₁-C₈-alkoxy, halogen and/or cyano,     -   or phenyl which is optionally mono- to pentasubstituted         identically or differently, where the substituents are each         selected from the list W¹,     -   or unsubstituted C₂-C₂₀-alkyl,     -   or C₁-C₂₀-alkyl which is mono- or polysubstituted, identically         or differently, by halogen, C₁-C₆-alkylthio,         C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxy,         C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-haloalkylthio,         C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl,         C₁-C₆-haloalkoxy, C₁-C₆-haloalkylamino,         halodi(C₁-C₆-alkyl)amino, —SiR¹R²R³ and/or C₃-C₆-cycloalkyl,         where the cycloalkyl moiety may in turn optionally be mono- to         tetrasubstituted, identically or differently, by halogen,         C₁-C₄-alkyl and/or C₁-C₄-haloalkyl, -   W¹ is halogen, cyano, nitro, amino, hydroxyl, C₁-C₈-alkyl,     C₁-C₈-alkoxy, C₁-C₈-alkylthio, C₁-C₈-alkylsulfinyl,     C₁-C₈-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆-alkenyloxy;     C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio,     C₁-C₆-haloalkylsulfinyl or C₁-C₆-haloalkylsulfonyl having in each     case from 1 to 13 identical or different halogen atoms;     C₂-C₆-haloalkenyl or C₂-C₆-haloalkenyloxy having in each case from 1     to 11 identical or different halogen atoms; C₃-C₆-cycloalkyl or     C₃-C₆-cycloalkyloxy; -   R¹ and R² are each independently hydrogen, C₁-C₈-alkyl,     C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl     or C₁-C₆-haloalkyl, -   R³ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,     C₁-C₄-alkylthio-C₁-C₄-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,     C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl,     C₃-C₆-cycloalkyl, or in each case optionally substituted phenyl or     phenylalkyl,     characterized in that -   5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride of the formula     (II)

is reacted with aniline derivatives of the formula (III)

in which R is as defined above, in the absence of an acid acceptor.

Surprisingly, the carboxamides of the formula (I) can be prepared under the inventive conditions with good yields in high purity and selectivity. A further advantage of the process according to the invention is that the workup is simpler, since the use of an acid acceptor is dispensed with. The process according to the invention also becomes more economically viable as a result. In addition, the reaction time can be shortened.

When, for example, 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride and 2-(1,3-dimethylbutyl)phenylamine are used as starting materials, the process according to the invention can be illustrated by the following formula scheme:

The 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride of the formula (II) used as a starting material in the performance of the process according to the invention is known (cf. EP-A 0 776 889).

The aniline derivatives also used as starting materials in the performance of the process according to the invention are defined in general by the formula (III).

-   R is preferably C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,     C₆-C₁₀-bicycloalkyl, C₂-C₇-oxacycloalkyl, C₄-C₇-oxacycloalkenyl,     C₃-C₇-thiacycloalkyl, C₄-C₇-thiacycloalkenyl, C₂-C₇-azacycloalkyl,     each of which may optionally be mono- to tetrasubstituted,     identically or differently, by C₁-C₄-alkyl, C₁-C₄-alkoxy, fluorine,     chlorine, bromine and/or cyano,     -   or phenyl which is mono- to trisubstituted identically or         differently, where the substituents are selected from the list         W¹,     -   or unsubstituted C₂-C,₂-alkyl (such as ethyl and straight-chain         or branched propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,         decyl, undecyl and dodecyl)     -   or C₁-C,₂-alkyl (such as methyl, ethyl and straight-chain or         branched propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,         decyl, undecyl and dodecyl) which is mono- or polysubstituted,         identically or differently, by fluorine, chlorine, bromine,         iodine, C₁-C₆-alkylthio, C₁-C₄-alkylsulfinyl,         C₁-C₄-alkylsulfonyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino,         di(C₁-C₄-alkyl)amino, C₁-C₄-haloalkylthio,         C₁-C₄-haloalkylsulfinyl, C₁-C₄-haloalkylsulfonyl,         C₁-C₄-haloalkoxy, C₁-C₄-haloalkylamino, halodi(C₁-C₄-alkyl)amino         having in each case from 1 to 9 fluorine, chlorine and/or         bromine atoms, —SiR¹R²R³, cyclopropyl, dichlorocyclopropyl,         cyclobutyl, cyclopentyl or cyclohexyl. -   R is more preferably cyclopentyl, cyclohexyl, cycloheptyl,     bicyclo[2.2.1]heptyl, or mono4-substituted phenyl, phenyl     disubstituted identically or differently in the 3,4-, 2,3-, 2,4- or     3,5-position, or phenyl trisubstituted identically or differently in     the 2,4,6-position, where the substituents are each selected from     the list W¹,     -   or unsubstituted C₃-C₁₀-alkyl (such as propyl, 1-methylethyl,         butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,         n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,         1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,         1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl,         3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl,         1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl,         2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,         1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl,         1-ethyl-3-methylpropyl, n-heptyl, 1-methylhexyl, 1-ethylpentyl,         2-ethylpentyl, 1-propylbutyl, octyl, 1-methylheptyl,         2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 1-propylpentyl,         2-propylpentyl, nonyl, 1-methyloctyl, 2-methyloctyl,         1-ethylheptyl, 2-ethylheptyl, 1-propylhexyl, 2-propylhexyl,         decyl, 1-methylnonyl, 2-methylnonyl, 1-ethyloctyl, 2-ethyloctyl,         1-propylheptyl and 2-propylheptyl) or C₁-C₁₀-alkyl (such as         methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,         2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl,         2-methylbutyl, 3-methylbutyl, 1,2-di-methylpropyl,         1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,         1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,         1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-di-methylbutyl,         1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,         1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,         2-ethylbutyl, 1-ethyl-3-methylpropyl, n-heptyl, 1-methylhexyl,         1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, octyl,         1-methylheptyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl,         1-propylpentyl, 2-propylpentyl, nonyl, 1-methyloctyl,         2-methyloctyl, 1-ethylheptyl, 2-ethylheptyl, 1-propylhexyl,         2-propylhexyl, decyl, 1-methylnonyl, 2-methylnonyl,         1-ethyloctyl, 2-ethyloctyl, 1-propylheptyl and 2-propylheptyl)         which is mono- or polysubstituted identically or differently by         fluorine, chlorine, methylthio, ethylthio, n- or isopropylthio,         n-, iso-, sec-, tert-butylthio, pentylthio, hexylthio,         methylsulfonyl, ethylsulfonyl, n- or isopropylsulfonyl, n-,         iso-, sec-, tert-butylsulfonyl, methoxy, ethoxy, n- or         isopropoxy, n-, iso-, sec-, tert-butoxy, methylamino,         ethylamino, n- or isopropylamino, n-, iso-, sec-,         tert-butylamino, dimethylamino, diisopropylamino,         trifluoromethylthio, trifluoromethoxy, —SiR¹R²R³, cyclopropyl,         dichlorocyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. -   W¹ is preferably fluorine, chlorine, bromine, methyl, ethyl, n- or     i-propyl, n-, i-, s- or t-butyl, methoxy, ethoxy, n- or i-propoxy,     trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy,     difluorochloromethoxy, trifluoroethoxy. -   W¹ is more preferably fluorine, chlorine or bromine. -   R¹ and R² are each independently preferably C₁-C₆-alkyl,     C₁-C₆-alkoxy, C₁-C₃-alkoxy-C₁-C₃-alkyl or     C₁-C₃-alkylthio-C₁-C₃-alkyl. -   R¹ and R² are each independently more preferably methyl, ethyl,     methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl,     ethoxyethyl, methylthiomethyl, ethylthiomethyl, methylthioethyl or     ethylthioethyl. -   R¹ and R² are each independently most preferably methyl, methoxy,     methoxymethyl or methylthiomethyl. -   R¹ and R² are especially preferably each methyl. -   R³ is preferably C₁-C₆-alkyl, C₁-C₆-alkoxy,     C₁-C₃-alkoxy-C₁-C₃-alkyl, C₁-C₃-alkylthio-C₁-C₃-alkyl,     C₃-C₆-cycloalkyl, phenyl or benzyl. -   R³ is more preferably methyl, ethyl, n- or isopropyl, n-, sec-, iso-     or tert-butyl, methoxy, ethoxy, n- or isopropoxy, n-, sec-, iso- or     tert-butoxy, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,     methylthiomethyl, ethylthiomethyl, methylthioethyl, ethylthioethyl,     cyclopropyl, phenyl or benzyl. -   R³ is most preferably methyl, ethyl, n- or isopropyl, iso- or     tert-butyl, methoxy, isopropoxy, iso- or tert-butoxy. -   R³ is especially preferably methyl.

Preference is given to using aniline derivatives of the formula (III-1)

in which R is as defined above, in the process according to the invention.

Preference is also given to using aniline derivatives of the formula (III-2)

in which R is as defined above, in the process according to the invention.

Preference is also given to using aniline derivatives of the formula (III-3)

in which R is as defined above, in the process according to the invention.

Particular preference is given to using aniline derivatives of the formula (III-1).

Aniline derivatives of the formula (III) or (III-1), (III-2) and (III-3) are known or can be prepared in a known manner (cf. EP-A 0 776 889, WO 03/010149).

The process according to the invention can be performed in the presence of a diluent. Useful diluents for this purpose include all inert organic solvents, preferably aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide, more preferably chlorobenzene or toluene.

The reaction temperatures in the performance of the process according to the invention can be varied within a relatively wide range. In general, temperatures of from 120° C. to 150° C., preferably temperatures of from 130° C. to 140° C., are employed.

In the performance of the process according to the invention, generally between 0.8 and 1.5 mol, preferably equimolar amounts, of aniline derivatives of the formula (III) are used per mole of the 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride of the formula (II).

Depending on the reactivity of the reactants, the reaction time may be up to 10 hours, but the reaction can also be terminated even earlier in the case of complete conversion. Preference is given to reaction times of 5 hours.

All processes according to the invention are generally performed under standard pressure. However, it is possible to work under elevated or reduced pressure—generally between 0.1 bar and 10 bar.

The carboxamides of the formula (I) preparable by the process according to the invention are value fungicides (cf, for example, WO 03/010149).

The inventive preparation of carboxamides of the formula (I) is described in the examples which follow, which further illustrate the above description. However, the examples should not be interpreted in a restrictive manner.

PREPARATION EXAMPLES

Under protective gas (argon), a solution of 2-(1,3-dimethylbutyl)phenylamine 18.05 g (100 mmol) in 40 ml of chlorobenzene is initially charged. 16.17 g (100 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride are added and the mixture is stirred at 130° C. for a further 5 h. For workup, the mixture is allowed to cool, 100 ml of water are added and the mixture is extracted three times with 100 ml each time of ethyl acetate. The combined organic phases are washed once with 100 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting suspension is stirred at room temperature with 100 ml for a further 2 h. This gives 28.2 g (89% of theory) of N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide in the form of crystals (melting point 104-106° C.). 

1. A process for preparing a carboxamide of formula (I)

in which R is C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₆-C₁₂-bicycloalkyl, C₂-C₁₂-oxacycloalkyl, C₄-C₁₂-oxacycloalkenyl, C₃-C₁₂-thiacycloalkyl, C₄-C₁₂-thiacycloalkenyl, C₂-C₁₂-azacycloalkyl, each of which may optionally be mono- or polysubstituted, identically or differently, by C₁-C₈-alkyl, C₁-C₈-alkoxy, halogen and/or cyano, or phenyl which is optionally mono- to pentasubstituted identically or differently, where the substituents are each selected from the list W¹, or unsubstituted C₂-C₂₀-alkyl, or C₁-C₂₀-alkyl which is mono- or polysubstituted, identically or differently, by halogen, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxy, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylamino, halodi(C₁-C₆-alkyl)amino, —SiR¹R²R³ and/or C₃-C₆-cycloalkyl, where the cycloalkyl moiety may in turn optionally be mono- to tetrasubstituted, identically or differently, by halogen, C₁-C₄-alkyl and/or C₁-C₄-haloalkyl, W¹ is halogen, cyano, nitro, amino, hydroxyl, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkylthio, C₁-Cs-alkylsulfinyl, C₁-Cs-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆-alkenyloxy; C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl or C₁-C₆-haloalkylsulfonyl having in each case from 1 to 13 identical or different halogen atoms; C₂-C₆-haloalkenyl or C₂-C₆-haloalkenyloxy having in each case from 1 to 11 identical or different halogen atoms; C₃-C₆-cycloalkyl or C₃-C₆-cycloalkyloxy; R¹ and R² are each independently hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl or C₁-C₆-haloalkyl, R³ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl, or in each case optionally substituted phenyl or phenylalkyl, said process comprising: reacting 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl fluoride of formula (II)

with aniline derivatives of formula (III)

in which R is as defined above, in the absence of an acid acceptor.
 2. The process as claimed in claim 1 wherein a temperature of from 120° C. to 150° C. are is employed.
 3. The process as claimed in claim 1, wherein an aniline derivative of the formula (III-1)

is used.
 4. The process as claimed in claim 1 wherein 2-(1,3-dimethylbutyl)phenylamine is used as the aniline derivative of the formula (III).
 5. The process as claimed in claim 2, wherein a temperature of from 120° C. to 150° C. is employed.
 6. The process as claimed in claim 2, wherein 2-(1,3-dimethylbutyl)phenylamine is used as the aniline derivative of the formula (III).
 7. The process as claimed in claim 3, wherein 2-(1,3-dimethylbutyl)phenylamine is used as the aniline derivative of the formula (III).
 8. A carboxamide of formula I

in which R is C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₆-C₁₂-bicycloalkyl, C₂-C₁₂-oxacycloalkyl, C₄-C₁₂-oxacycloalkenyl, C₃-C₁₂-thiacycloalkyl, C₄-C₁₂-thiacycloalkenyl, C₂-C₁₂-azacycloalkyl, each of which may optionally be mono- or polysubstituted, identically or differently, by C₁-C₈-alkyl, C₁-C₈-alkoxy, halogen and/or cyano, or phenyl which is optionally mono- to pentasubstituted identically or differently, where the substituents are each selected from the list W¹, or unsubstituted C₂-C₂₀-alkyl, or C₁-C₂₀-alkyl which is mono- or polysubstituted, identically or differently, by halogen, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxy, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C₆-haloalkylsulfonyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylamino, halodi(C₁-C₆-alkyl)amino, —SiR¹R²R³ and/or C₃-C₆-cycloalkyl, where the cycloalkyl moiety may in turn optionally be mono- to tetrasubstituted, identically or differently, by halogen, C₁-C₄-alkyl and/or C₁-C₄-haloalkyl, W¹ is halogen, cyano, nitro, amino, hydroxyl, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkylthio, C₁-C₈-alkylsulfinyl, C₁-C₈-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆-alkenyloxy; C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, C₁-C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl or C₁-C₆-haloalkylsulfonyl having in each case from 1 to 13 identical or different halogen atoms; C₂-C₆-haloalkenyl or C₂-C₆-haloalkenyloxy having in each case from 1 to 11 identical or different halogen atoms; C₃-C₆-cycloalkyl or C₃-C₆-cycloalkyloxy; R¹ and R² are each independently hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl or C₁-C₆-haloalkyl, R³ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylthio-C₁-C₄-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl, or in each case optionally substituted phenyl or phenylalkyl, that has been prepared in the absence of an acid acceptor. 